CNS deletion of Pten in the mouse has revealed its roles in controlling cell size and number, thus providing compelling etiology for macrocephaly and Lhermitte-Duclos disease. In the present study, we deleted Pten in a limited differentiated neuronal population, the dopamine neurons of the ventral midbrain. Resulting mutant mice are currently under study in our laboratory. We observed neuronal hypertrophy in the substantia nigra and VTA. However, this abnormal morphology was not associated with behavioral changes after acute and chronic exposure to cocaine, as measured by locomotor activity. Also, while dopamine levels were clearly upregulated in the SN and VTA they remained unchanged in the striatum of young animals. Thus, our data suggest that abnormal activation of the PTEN-PI3K/AKT pathway in dopamine neurons increases the number and size of this neuronal population, but it does not appear to alter behavior or the distribution of dopamine in the striatum. Also, enkephaline and dynorphine levels remained unchanged in the PTEN knockout animals. Studies in aged animals will be necessary to determine if PTEN ablation is detrimental for the dopaminergic system neurons during aging.